Selective inhibition of the activity of neuronal nitric oxide synthase (nNOS) over its closely related isoforms, inducible NOS (iNOS) and endothelial NOS (eNOS), has attracted considerable attention as a target for the treatment of various neurodegenerative diseases such as Parkinson's, Alzheimer's, Huntington's disease, and cerebral palsy. A variety of small molecule scaffolds have been identified that selectively inhibit the activity of nNOS. As part of an effort to find new inhibitors of nNOS, compound 1 was recently prepared and identified as a very potent (Ki=5 nM) and highly selective (3800-selective over endothelial NOS, 1200-fold over inducible NOS) nNOS inhibitor. Animal tests demonstrated that 1 could lead to a remarkable reduction in neurological damage to rabbit fetuses under hypoxic conditions. On the basis of these positive results, compound 1 has become a promising lead for further investigation.

Despite this exciting discovery, it is still difficult to achieve gram-scale quantities of 1 for a comprehensive preclinical study because of its challenging synthesis. The previously reported synthetic procedure, shown in Scheme 1, involves 13 steps starting from 4,6-dimethyl-2-aminopyridine. Although this synthesis successfully produced 1, several factors limit scalability. The route was long, and many steps suffered from low yields, resulting in an overall yield of approximately 0.5%. More importantly, the late stage benzyl-deprotection step, involving catalytic hydrogenation of the N-Boc-N-benzyl-protected aminopyridine intermediate 2 (Scheme 1) using a variety of catalytic hydrogenation conditions, proceeded poorly to give 3 with low isolated yields (5-25%).

Furthermore, the strong reducing conditions used to remove the benzyl-protecting group prohibited the incorporation of reducible functional groups (e.g., nitriles, ketones, alkenes, and halophenyls) into new inhibitors, which significantly limited the structure-activity relationship study of this scaffold. For instance, as summarized in Scheme 2, attempts to synthesize 4 with a similar synthetic route to that of 1 failed because removal of the benzyl-protecting group of 5 using different hydrogenation conditions led to phenyl dehalogenation (6). Removal of the benzyl-protecting group of 7 by catalytic hydrogenation, on the other hand, led to partial reduction of the cyclopropyl ring (8). In addition, the strong reducing conditions led to the reduction of the pyridinyl group in 9 to generate piperidinyl compound 11. Because of the aforementioned difficulties, there remains the need for a more efficient, scalable, and potentially more versatile synthesis of 1 (and related pyrrolidine compounds).
